Loss of α7nAChR enhances endothelial-to-mesenchymal transition after myocardial infarction via NF-κB activation.

The myocardial fibrosis in response to myocardial infarction (MI) is closely related to the dysbalance of endothelial-to-mesenchymal transition (EndMT). Although numerous reports indicate that α7 nicotinic acetylcholine receptor (α7nAChR) activates the cholinergic anti-inflammatory pathway (CAP) to regulate the magnitude of inflammatory responses, the role of α7nAChR in myocardial fibrosis, as well as the underlying mechanisms, have not been elucidated. In this study, we evaluated cardiac function, fibrosis, and EndMT signaling using a mouse model of MI and interleukin (IL)-1ß-induced human cardiac microvascular endothelial cells (HCMECs). In vivo, α7nAChR deletion increased cardiac dysfunction, exacerbated the cardiac inflammatory response, and NF-κB activation, and enhanced EndMT, as shown by higher expression levels of fibroblast markers (FSP-1, α-SMA, collagen I, Snail) and decreased levels of the FGFR1, glucocorticoid receptor (GR) and endothelial marker (CD31) compared to wild-type mice. In vitro, the pharmacological activation of α7nAChR with PNU282987 significantly inhibited IL-1ß-induced EndMT, as shown by a reduced transition to the fibroblast-like phenotype and the expression of fibrotic markers. Moreover, the IL-1ß-mediated activation of NF-κB pathway was suppressed by PNU282987. This anti-EndMT effect of α7nAChR was associated with regulation of Snail. Furthermore, Western blot analysis further revealed that the GR antagonist RU38486 could partially counteract the effect of PNU282987 on NF-κB expression. In conclusion, our results show that α7nAChR is involved in cardiac fibrosis by inhibiting EndMT, providing a novel approach to the treatment of MI.

Combined Systemic Immune-inflammatory Index (SII) and Geriatric Nutritional Risk Index (GNRI) predict survival in elderly patients with hip fractures: a retrospective study.

PURPOSE: The Systemic Immune-inflammatory Index (SII) and Geriatric Nutritional Risk Index (GNRI) have undergone comprehensive examination and validation in forecasting the outcomes of diverse medical conditions. Nevertheless, the correlation between the combined use of GNRI and SII metrics and hip fractures has yet to be elucidated. This study aimed to determine whether the amalgamation of SII and GNRI scores constitutes an independent prognostic factor for elderly patients with hip fractures. METHODS: We conducted a retrospective analysis of elderly patients admitted to our facility with hip fractures, encompassing both femoral neck and intertrochanteric fractures. Demographic information, experimental parameters, and postoperative complications were systematically recorded. The Geriatric Nutritional Risk Index (GNRI) and Systemic Immunoinflammatory Index (SII) were meticulously computed. Receiver operating characteristic (ROC) curves were generated, and optimal cutoff values for each parameter were determined. Subsequently, a multivariate Cox regression analysis was employed to assess the predictive utility of the SII-GNRI score in relation to 1-year postoperative mortality among elderly patients with hip fractures. RESULTS: In a study involving 597 patients, 90 of whom experienced mortality within 1 year, it was observed that the SII-GNRI score in the group of patients who passed away was significantly higher compared to the group that survived. Following a multifactorial adjustment, it was established that a high SII-GNRI score served as an independent predictor of 1-year all-cause mortality in older patients with hip fractures. In addition to the SII-GNRI score, factors such as length of hospital stay, CCI > 2, and blood transfusion were also identified as independent risk factors for survival. Notably, the incidence of postoperative complications in patients with high SII-GNRI scores was significantly greater than in patients with low scores. CONCLUSION: The SII-GNRI score proves valuable in predicting the 1-year survival rate for elderly patients with hip fractures who have undergone surgery.

Autophagy in Atherosclerotic Plaque Cells: Targeting NLRP3 Inflammasome for Self-Rescue.

Atherosclerosis (AS) is a lipid-driven disorder of the artery intima characterized by the equilibrium between inflammatory and regressive processes. A protein complex called NLRP3 inflammasome is involved in the release of mature interleukin-1ß (IL-1ß), which is connected to the initiation and progression of atherosclerosis. Autophagy, which includes macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, is generally recognized as the process by which cells transfer their constituents to lysosomes for digestion. Recent studies have suggested a connection between vascular inflammation and autophagy. This review summarizes the most recent studies and the underlying mechanisms associated with different autophagic pathways and NLRP3 inflammasomes in vascular inflammation, aiming to provide additional evidence for atherosclerosis research.

Activation of the alpha 7 nicotinic acetylcholine receptor mitigates osteoarthritis progression by inhibiting NF-κB/NLRP3 inflammasome activation and enhancing autophagy.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation. Alpha 7 nicotinic acetylcholine receptor (α7nAChR) is associated with inflammatory and metabolic responses in OA. However, the mechanisms underlying the pathological process of OA remain unclear. The aim of the present study was to examine the role and mechanisms of α7nAChR-mediated autophagy and anti-inflammatory response in chondroprotection. Monosodium iodoacetate (MIA)-induced Wistar rat OA model was used to assess the in vivo effects of the ɑ7nAChR agonist (PNU-282987). The histopathological characteristics of OA were evaluated by immunohistochemistry (IHC), and the levels of autophagy markers were determined by western blotting and transmission electron microscopy. The anti-inflammatory effect of the ɑ7nAChR agonist was assessed by IHC, quantitative real-time polymerase chain reaction, and western blotting. Parallel experiments to determine the molecular mechanisms through which the ɑ7nAChR agonist prevents OA were performed using interleukin-1ß (IL-1ß)-treated chondrocytes. Our results showed that PNU-282987 reduced cartilage degeneration and matrix metalloproteinase (MMP)-1 and MMP-13 expressions. Activating α7nAChR with PNU-282987 significantly promoted MIA/IL-1ß-induced chondrocyte autophagy, as demonstrated by the increase in LC3-II/LC3-I ratio, Beclin-1 levels, and autophagosome number. Furthermore, treating chondrocyte with ULK1 siRNA attenuated the PNU282987-induced enhancement of LC3-II/LC3-I ratio and Beclin-1 level. Additionally, PNU282987 suppressed NF-κB/NLRP3 inflammasome activation by inhibiting the ROS/TXNIP pathway and suppressed tumor necrosis factor-ɑ and IL-1ß secretion in MIA/IL-1ß-treated chondrocytes. Our results demonstrate that the activation of α7nAChR promotes chondrocyte autophagy and attenuates inflammation to mitigate OA progression, providing a novel target for the treatment of OA.

Klotho improves diabetic cardiomyopathy by suppressing the NLRP3 inflammasome pathway.

AIMS: NLRP3 inflammasome activation is essential for the development and prognosis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho is suggested to modulate tissue inflammatory responses. The aim of the present study was to examine the protective effects of Klotho on DCM. MAIN METHODS: A streptozotocin-induced diabetes mouse model was established to assess the effects of Klotho in vivo, which was administered for 12 weeks. The characteristics of type 1 DCM were evaluated by general status, echocardiography, and histopathology. The expression of associated factors was determined by RT-qPCR and western blotting. Parallel experiments to determine the molecular mechanism through which Klotho prevents DCM were performed using H9C2 cells exposed to high glucose (35 mM). KEY FINDINGS: Diabetes-induced increases in serum creatine kinase-muscle/brain and lactate dehydrogenase levels, cardiac fibrosis, cardiomyocyte apoptosis, and cardiac dysfunction were ameliorated by Klotho. Additionally, Klotho suppressed TXNIP expression, NLRP3 inflammasome activation, and expression of the inflammatory cytokines tumor necrosis factor ɑ, interleukin-1ß, and interleukin-18 in vivo. In high glucose-cultured cardiomyocytes, Klotho and N-acetylcysteine significantly downregulated intracellular reactive oxygen species generation and TXNIP/NLRP3 inflammasome activation. Pretreatment of H9C2 cells with NLRP3 siRNA or Klotho prevented high glucose-induced inflammation and apoptosis in H9C2 cells. SIGNIFICANCE: Our results demonstrate that the protective effect of Klotho on diabetes-induced cardiac injury is associated with inhibition of the NLRP3 inflammasome pathway, suggesting its therapeutic potential for DCM.